This invention relates to novel N-alkyl-N-acyl derivatives (I) of the antibiotic thienamycin (structure II, below). Such compounds, including their O- and carboxyl derivatives and their pharmaceutically acceptable salts are useful as antibiotics. This invention also relates to processes for the preparation of such compounds, pharmaceutical compositions comprising such compounds, and methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated. The compounds of the present invention may generically be represented by the following structural formula (I): ##STR2## or, more conveniently, by the symbol: ##STR3## wherein: "Th" symbolizes the bicyclic nucleus of thienamycin and the OH, amino, and carboxyl groups of thienamycin are illustrated;
R.sup.2 is acyl (the term "acyl" is by definition inclusive of the alkanoyls including derivatives and analogues thereof such as thio analogues wherein the carbonyl oxygen is replaced by sulphur, as well as the sulphur and phosphorous acyl analogues such as substituted sulfonyl-, sulfinyl- and sulfenyl- radicals and substituted P (III and V) radicals such as the substituted phosphorous-, phosphoric-, phosphonous- and phosphonic- radicals, respectively; such acyl radicals of the present invention are further defined below); PA1 X is oxygen, sulphur or NR' (R'=H or alkyl having 1-6 carbon atoms); and R.sup.4 is, inter alia, representatively selected from the group consisting of hydrogen, conventional blocking groups such as trialkylsilyl, acyl and radicals (R.sup.4) giving rise to the pharmaceutically acceptable salt, ester and amide moieties (--COXR.sup.4) known in the bicyclic .beta.-lactam antibiotic art (the definition of R.sup.4 is given in greater detail below); PA1 R.sup.3 is hydrogen; or PA1 R.sup.3 is (1) acyl (generically the group OR.sup.3 is classifiable as an ester); or (2) R.sup.3 is selected from alkyl, aryl, aralkyl and the like (such that the group OR.sup.3 is generically classifiable as an ether); the term "acyl" is by definition inclusive of the alkanoyls including derivatives and analogues thereof such as thio analogues wherein the carbonyl oxygen is replaced by sulphur; as well as sulphur and phosphorous acyl analogues such as substituted sulfonyl-, sulfinyl-, and sulfenyl- radicals, and substituted P (III and V) radicals such as substituted phosphorous-, phosphoric-, phosphonous- and phosphonic- radicals, respectively; such acyl radicals of the present invention are further defined below, as are the radicals (2, above) which constitute the ether embodiments of the present inventon; and PA1 R.sup.1 is, inter alia, alkyl, alkenyl, aryl or aralkyl; for example, R.sup.1 may be selected from the group consisting of: substituted and unsubstituted: lower alkyl having 1-10 carbon atoms, alkenyl having 2-10 carbon atoms, alkynyl having 2-10 carbon atoms, ring substituted and unsubstituted: cycloalkyl, cycloalkenyl, cycloalkenylalkyl, and cycloalkylalkyl having 3-6 ring carbon atoms and 1-6 carbon atoms in the alkyl chain; aryl having 6-10 carbon atoms; aralkyl having 6-10 ring carbon atoms, and 1-6 carbon atoms in the alkyl chain; mono- and bicyclic heteroaryl and heteroaralkyl comprising 4-10 ring atoms one or more of which is selected from oxygen, nitrogen and sulphur and 1-6 carbon atoms in the alkyl chain; and wherein the ring or chain substituent (or substituents) in the aforementioned radicals is selected from: halo such as chloro, bromo, iodo and fluoro, azido, cyano, amino, mono-, di- and trialkyl substituted amino wherein the alkyl has 1-6 carbon atoms, hydroxyl, alkoxyl having 1-6 carbon atoms, alkylthioalkyl having 1-6 carbon atoms, carboxyl, oxo, alkoxycarbonyl having 1-6 carbon atoms in the alkoxyl moiety, acyloxy comprising 2-10 carbon atoms, carbamoyl, and mono- and dialkylcarbamoyl wherein the alkyl groups have 1-4 carbon atoms, cyanothio (--SCN), and nitro; PA1 R.sup.1 is further defined below.
Thienamycin, a convenient starting material for the preparation of the compounds of the present invention, is disclosed and claimed in U.S. Pat. No. 3,950,357, issued Apr. 13, 1976. This patent is incorporated herein by reference for the disclosure relative to the preparation and isolation of thienamycin. Thienamycin is known to have the following structure (II): ##STR4## Starting material II (including all isomers and mixtures of isomers thereof) is also available by the total synthesis which is described and claimed in co-pending, commonly assigned U.S. patent application Ser. No. 792,071, filed Apr. 28, 1977, of Christensen, Johnston and Schmitt, now abandoned. This application is incorporated herein by reference since it makes available all isomers, pure and as mixtures, of II which are suitable starting materials for the preparation of the compounds of the present invention. Another convenient starting material for preparation of the compounds of the present invention is N-alkylated thienamycin and its O- and carboxyl derivatives (III): ##STR5## wherein R.sup.3, X, R.sup.4 and R.sup.1 are as defined above. The N-alkylated thienamycins (III) are disclosed and claimed in co-pending U.S. patent application Ser. No. 733,611 filed Oct. 18, 1976, now abandoned. This application is incorporated herein by reference for its disclosure relative to the preparation of N-alkyl thienamycins defined by III, above.
There is a continuing need for new antibiotics. For unfortunately there is no static effectiveness of a given antibiotic because continued wide scale usage of any such antibiotic selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly the search for new antibiotics continues.
Unexpectedly, it has been found that the compounds of the present invention are broad spectrum antibiotics, which are useful in animal and human therapy and in inanimate systems.
Thus, it is an object of the present invention to provide a novel class of antibiotics which possess the basic nuclear structure of the antibiotic thienamycin but which are characterized as N-alkyl-N-acyl derivatives thereof. These antibiotics are active against a broad range of pathogens which representatively include gram positive bacteria such as S. aureus, Strep. pyogenes and B. subtilis and gram negative bacteria such as E. coli, Proteus morganii, Serratia and Klebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salts; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and composition when an antibiotic effect is indicated.